PROJECT SUMMARY/ABSTRACT Dr. Joel Salinas is a Behavioral Neurologist and Neuropsychiatrist at Massachusetts General Hospital (MGH), whose career goal is to become a leading clinician-investigator in the field of brain aging with specific emphasis in understanding the socio-behavioral aspects of Alzheimer's disease (AD). These insights will help identify underlying biological pathways in AD risk and disease progression and, eventually, characterize more patient- centered interventions and outcomes in the treatment of AD. As a first step towards this goal, he seeks to improve the study of social relationship factors in AD by developing effective methods for quantifying and identifying relevant social phenotypes. This area of AD research is promising because factors like loneliness and social isolation have been tied to accumulation of AD-related neuropathology, but the biological underpinnings of these influences remain poorly understood. A critical barrier to improving our understanding of these pathways is addressing the complexity of social relationship factors and temporally relating these to biological changes and disease risk. To overcome this barrier, Dr. Salinas's proposal seeks to use a large, well-characterized, community-based longitudinal cohort to investigate whether social relationship factors?when quantified at the level of two major subcomponents, social support and social network graphs?1) prospectively affect risk for incident AD and 2) are associated with vulnerability for AD-related neurodegeneration and cognitive decline. Dr. Salinas plans to employ a research approach that systematically relates social phenotypes to neuropsychological testing, cutting-edge neuroimaging, and clinical assessments most relevant in the earliest stages of AD. Dr. Salinas established an early-career track record in the investigation of neuroimaging markers of development as well as the psychosocial determinants and epidemiology of poststroke depression, acquiring foundational expertise in statistics and bioinformatics in the process. As part of a mentored T32 award, he also generated preliminary data supporting the feasibility of the proposed research. The proposed K23 award will train Dr. Salinas in selection, capture, and interpretation of social relationship measures, social network graph model construction and analysis, and advanced techniques in the medical epidemiology of aging. To this end, Dr. Salinas has assembled a team of experts in all aforementioned areas, leveraging the extensive resources and exceptional environment of Massachusetts General Hospital, Harvard Medical School, Harvard TH Chan School of Public Health, Boston University School of Medicine, and the Framingham Study networks. Dr. Sudha Seshadri will serve as primary mentor with Dr. Jonathan Rosand as co-mentor alongside an advisory committee of highly experienced members, including Drs. Lisa Berkman, Charles DeCarli, JP Onnela, and Reisa Sperling. This award will provide Dr. Salinas with the skills to evolve into an independent clinician-investigator at the forefront of AD quantitative social phenotyping, developing methods that may ultimately enhance AD research in observational cohorts and clinical trials.